The overall goal of this laboratory is to determine the molecular factors involved in age-related macular degeneration (AMD), a leading cause of blindness in the US. The pathophysiology of AMD is complex involving the natural aging process, genetics and environmental factors. Presently we are concentrating our efforts on studying the effects of oxidized cholesterol and the oxysterol binding proteins (OSBPs) in the retina and pigment epithelium. LDL, a major source of oxidized cholesterol, is known to accumulate in Bruch's membrane and the choriocapillaris during the normal aging process. Oxidized forms of cholesterol are known to have potent toxic pharmacological effects that can inhibit cholesterol synthesis and induce apoptosis in cells. We are investigating the possibility that the accumulation of these oxysterols in Bruch's membrane and the choriocapillaris may be contributing to the pathology of AMD by toxifying the retinal pigment epithelium. The OSBPs are a family of proteins that share similar structural domains and are known to bind oxysterols. We have isolated eleven different members of this family and determined their expression in a variety of human tissues. We have preliminary evidence suggesting that some of these protein may be serving as receptors rather than binding protein. We are also pursuing other approaches to studying AMD. We are screening 1100 AMD patients and age-matched controls for mutations in known retinal genes in an attempt to find a genetic correlation to the disease. This could help determine which biochemical pathways are failing and to formulate strategies for treatment and/or prevention.